We appreciate the comments of Dr Tsuda on our recent article “Elevated C-reactive protein and long-term mortality after ischemic stroke: relationship with markers of endothelial cell and platelet activation.”1
Dr Tsuda cites evidence of a direct effect of C-reactive protein (CRP) on eNOS (endothelial nitric oxide synthase) activity on aortic endothelial cells in vitro and the relationship between CRP and endothelium-dependent dilatation in healthy children as supportive of a potential influence of CRP on ischemic stroke outcome being mediated, at least in part, through impaired NO production and/or bioavailability. This is an interesting hypothesis; however, evidence in the literature suggests that the relationship between ischemic stroke and NO is complex with some studies suggesting that excessive NO production during the acute ischemic event may be cytotoxic. For instance, a study by Castillo et al demonstrated that increased NO metabolites in cerebrospinal fluid measured within 24 hours of acute ischemic stroke was associated with greater infarct volume, early neurological deterioration and poor outcome at 3 months.2 Conversely, Rashid and colleagues reported that plasma NO metabolites and l-arginine measured within 72 hours of acute ischemic stroke were significantly lower than in healthy controls and decreased NO metabolites and l-arginine predicted poor outcome.3 This conflicting clinical data are mirrored by results in experimental models of ischemic stroke carried out in mice deficient in different isoforms of NOS, with a protective effect demonstrated for eNOS in contrast to detrimental effects for the neuronal and inducible NOS isoforms.2
Because we have not analyzed plasma or urinary NO metabolites in our study, we are unable to shed any further light on whether NO is related to protective or adverse outcomes after ischemic stroke. Although we cannot provide any evidence to support the hypothesis that CRP plays a role in modulating NO production and bioavailability in ischemic stroke in our study, infusion of CRP has been shown to give rise to an ≈50% increase in plasma vWF and soluble E-selectin,4 suggesting that CRP may have a direct influence on endothelial function.
Shantikumar S, Grant PJ, Catto AJ, Bamford JM, Carter AM. Elevated C-reactive protein and long term mortality post-ischaemic stroke: relationship with markers of endothelial cell and platelet activation. Stroke. 2009; 40: 977–979.
Castillo J, Rama R, Dávalo A. Nitric oxide-related brain damage in acute ischemic stroke. Stroke. 2000; 31: 852–857.
Bisoendial RJ, Kastelein JJ, Levels JH, Zwaginga JJ, van den BB, Reitsma PH, Meijers JC, Hartman D, Levi M, Stroes ES. Activation of inflammation and coagulation after infusion of C-reactive protein in humans. Circ Res. 2005; 96: 714–716.